Two naturally occurring mutations of human GPR103 define distinct G protein selection bias

Ma, Qiang; Cao, Zheng; Li, Huanzheng; Wang, Weiwei; Yan, Tian; Yan, Lili; Yuan, Ling; Chen, Xiangnan; Chen, Yu; Shi, Ying; Tang, Shaohua; Zhou, Naiming

doi:10.1016/j.bbamcr.2021.119046

Cited by 4 publications

(3 citation statements)

References 67 publications

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“…We made use of the expression system to test whether sequestration of endogenous Gβγ subunits can block mTRPA1 activation by mCXCR2. Transfecting HEK293T cells with either Gαtransducin (Gαt) or the carboxy-terminal domain of G protein-coupled receptor kinase 2 (GRK2ct), which are both scavengers of Gβγ subunits [35][36][37] , significantly reduced mTRPA1 activation by mCXCR2 upon CXCL5 challenge (Fig. 4G).…”

Section: Exploring the Biochemical Basis Underlying Cxcr2-mediated Tr...mentioning

confidence: 99%

CXCL5 activates CXCR2 in nociceptive sensory neurons to drive joint pain and inflammation in experimental gouty arthritis

Yin,

Liu,

Dong

et al. 2024

Nat Commun

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Gouty arthritis evokes joint pain and inflammation. Mechanisms driving gout pain and inflammation remain incompletely understood. Here we show that CXCL5 activates CXCR2 expressed on nociceptive sensory neurons to drive gout pain and inflammation. CXCL5 expression was increased in ankle joints of gout arthritis model mice, whereas CXCR2 showed expression in joint-innervating sensory neurons. CXCL5 activates CXCR2 expressed on nociceptive sensory neurons to trigger TRPA1 activation, resulting in hyperexcitability and pain. Neuronal CXCR2 coordinates with neutrophilic CXCR2 to contribute to CXCL5-induced neutrophil chemotaxis via triggering CGRP- and substance P-mediated vasodilation and plasma extravasation. Neuronal Cxcr2 deletion ameliorates joint pain, neutrophil infiltration and gait impairment in model mice. We confirmed CXCR2 expression in human dorsal root ganglion neurons and CXCL5 level upregulation in serum from male patients with gouty arthritis. Our study demonstrates CXCL5-neuronal CXCR2-TRPA1 axis contributes to gouty arthritis pain, neutrophil influx and inflammation that expands our knowledge of immunomodulation capability of nociceptive sensory neurons.

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Section: Exploring the Biochemical Basis Underlying Cxcr2-mediated Tr...mentioning

confidence: 99%

CXCL5 activates CXCR2 in nociceptive sensory neurons to drive joint pain and inflammation in experimental gouty arthritis

Yin,

Liu,

Dong

et al. 2024

Nat Commun

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“…Characterization or design of biased GPCR agonists is now a promising approach to develop selective drugs with increased efficacy and reduced side effects [129][130][131]. Interestingly, it has been recently reported that the 26RFa peptide receptor GPR103 [132] is a Gαq and Gαi/o-dually coupled receptor and that two naturally occurring mutations Y68H and R371W exhibit distinct but opposite signaling bias, Gαq/PLC/Ca 2+ and Gβγ/PKCζ/ERK1/2, respectively [133]. For the obvious reasons given in the Introduction section, the concept of super-agonist cannot be applied to endogenous molecules.…”

Section: Characterization Of Agonismmentioning

confidence: 99%

Why Search for Alternative GPCR Agonists?

Boutin

Leprince

2023

Receptors

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Intuitively, it is easy to understand why we search for G protein-coupled receptor (GPCR) antagonists. It is obviously to block a functionality of a specific receptor potentially linked to some aspects of disease. Whether by focused research or by serendipity, many drugs were discovered in the last century that function as antagonist at a precise receptor. A current idea is that at least half of the drugs on the market are antagonist ligands of GPCRs. Then, why are we searching for alternative receptor agonists while the endogenous activating molecule is known? In the present commentary we try to rationalize these fields of research, since they proved to be very successful over the years, with receptor pharmacology populated with dozens of alternative agonists, particularly to bioaminergic receptors, and to a lesser extent to peptidergic ones. However, the action of such compounds is not well-characterized: are they surrogates to the endogenous agonist, and if yes in which context and for which purpose? The present essay is a reflection on this subject that leads to fundamental interrogations of our understanding of GPCR roles and functions.

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“…However, Gq-and Gi/o-mediated signaling was also reported [11,25]. Two naturally occurring mutations in the human QRFP receptor lead to distinct and opposite 26RFa-evoked signaling bias [20].…”

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confidence: 99%

QRFP receptor in GtoPdb v.2023.1

Bagnol

Bonner²,

Carlebur

et al. 2023

GtoPdb CITE

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The human gene encoding the QRFP receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the QRFP receptor [19]; QRFPR, formerly known as the Peptide P518 receptor), previously designated as an orphan GPCR receptor was identified in 2001 by Lee et al. from a hypothalamus cDNA library [17]. However, the reported cDNA (AF411117) is a chimera with bases 1-127 derived from chromosome 1 and bases 155-1368 derived from chromosome 4. When corrected, QRFPR (also referred to as SP9155 or AQ27) encodes a 431 amino acid protein that shares sequence similarities in the transmembrane spanning regions with other peptide receptors. These include neuropeptide FF2 (38%), neuropeptide Y2 (37%) and galanin Gal1 (35%) receptors. QRFP receptor was identified as a Gs-coupled GPCR [6, 14] that's activated by the endogenous peptides QRFP43 (43RFa) and QRFP26 (26RFa) [6, 14, 11]. However, Gq- and Gi/o-mediated signaling was also reported [11, 25]. Two naturally occurring mutations in the human QRFP receptor lead to distinct and opposite 26RFa-evoked signaling bias [20].

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Two naturally occurring mutations of human GPR103 define distinct G protein selection bias

Cited by 4 publications

References 67 publications

CXCL5 activates CXCR2 in nociceptive sensory neurons to drive joint pain and inflammation in experimental gouty arthritis

CXCL5 activates CXCR2 in nociceptive sensory neurons to drive joint pain and inflammation in experimental gouty arthritis

Why Search for Alternative GPCR Agonists?

QRFP receptor in GtoPdb v.2023.1

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